PROJECT SUMMARY Kratom, also known as Mitragyna speciosa, is a controversial plant in the coffee family that contains more than 20 alkaloids, several of which are biologically active, with mitragynine being the most prevalent. Kratom has a fascinating, and mixed, pharmacological profile that combines opioid and stimulant effects, with stimulant effects being most prevalent at low-to-moderate doses and opioid effects presenting with higher doses. Although kratom has been used for centuries in Southeast Asia to counteract fatigue and manage pain, opioid withdrawal, fever and depression, its increased use in the United States has recently been the subject of a FDA public health advisory addressing adverse risks and abuse liability associated with its use. Unfortunately, most information regarding kratom pharmacology has been derived anecdotally from human users. The decisions that scientists, clinicians, and government officials face regarding the potential scheduling of kratom as a controlled substance is limited by a lack of preclinical, experimental data obtained from laboratory animals. While the addictive properties of kratom have garnered the most public attention and are likely due to mu opioid receptor activation, it is the stimulant effects of kratom, likely resulting from enhanced adrenergic transmission, that are especially understudied and perhaps most relevant to its therapeutic potential. Our goal in this R21 application is to provide the first comprehensive study of a kratom alkaloid (mitragynine) in preclinical models of neuropathic pain and self-administration (SA) and to define, and discriminate, the neuroprotective and reinforcing efficacies of mitragynine in terms of receptor mechanisms and sites of action. The overall hypothesis to be tested using rats is that mitragynine reduces chemotherapy-induced neuropathic pain by enhancing adrenergic transmission at ?2-adrenoceptors and produces reinforcing and motivational effects in self-administration assays through mu opioid receptor activation. The expected positive impact of our study is the first preclinical characterization of a kratom alkaloid against neuropathic pain and the delineation, and separation, of underlying mechanisms of analgesia and reinforcement that will better define the therapeutic potential and abuse liability of kratom constituents.